Method for preparation of well-dispersed, discrete nanoparticles by spray drying techniques

ABSTRACT

A method for preparing uniquely sized nanoparticles of CaF 2  by simultaneously spray drying a first NH 4 F and a biocompatible salt solution and a second Ca(OH) 2  and biocompatible salt solution to form CaF 2  solid particles in a soluble salt matrix wherein the salt is more soluble than CaF 2 . The salt matrix may then be dissolved and the separate CaF 2  nanosized particles collected for use as a dental therapeutic material. The technique is useful in the preparation of other discrete, nanoparticle sized compounds and combinations by carefully choosing the solvents and solutes of the two spray dried solutions.

CROSS REFERENCE TO RELATED APPLICATION

This is a utility application incorporating by reference and claimingpriority to previously filed provisional application Ser. No. 61/447,504filed Feb. 28, 2011 entitled “Method for Preparation of Well-DispersedCaF₂ Nanoparticles by Spray Drying Techniques”.

BACKGROUND OF THE INVENTION

In a principal aspect, the present invention relates to a spray dryingprocess for preparation of discrete nanosized particles, such as CaF₂particles, that are not agglomerated.

Calcium fluoride (CaF₂) or ‘CaF₂-like’ materials are of significantinterest in caries prevention as they have been suggested to be themajor source of labile fluoride (F) in the oral environment after Ftreatments. The release of F from the labile store of loosely bound F inthe oral cavity environment increases the mineral saturation of oralfluid, and can promote the repair of lesions and reduce demineralizationduring cariogenic attack. However, a conventional sodium fluoride (NaF)rinse can only lead to very small amounts of CaF₂ deposit formation dueto the low concentration of free calcium (Ca) ions in the mouth. Incontrast, more CaF₂ deposits in the oral environment have been found tosignificantly increase the remineralization effects of the F treatmentwithout increasing the F levels.

Previously reported is the preparation of a nano CaF₂ that has atheoretical spherical particle size of 41 nm based on BET(Brunauer-Emmett-Teller) surface area measurements. When used as the Fsource in an oral rise, these nano CaF₂ were shown to produce a greaterF deposition than a NaF rinse of the same F dose in both in vitro and invivo studies. However, electron microscopic observations indicated thatthe CaF₂ material consisted primarily of CaF₂ agglomerates, about 300 nmto 800 nm in size, but that the agglomerates, were made up of much smallprimary CaF₂ particles of <50 nm in size. These agglomerates were notreadily dispersed into the primary CaF₂ particles by ultrasoundprocessing, indicating that the primary CaF₂ particles in each clusterwere tightly held together. However, there is strong evidence thatsignificantly greater F efficacies can be achieved if the nano CaF₂ oragglomerates can be dispersed into the smaller primary particles.Unwanted agglomeration of nanoparticles due either to the preparationprocess or post synthesis treatments has thus remained a problem.

SUMMARY OF THE INVENTION

Briefly, the present invention comprises a method or process forpreparation of dispersed nanosized particles, such as CaF₂ particles, byforming the particles in a soluble salt matrix, such as NaCl, using aspray drying apparatus similar in some aspects to that reported inPreparation and properties of nano-sized calcium fluoride for dentalapplications. Dent Mater 2008;24(1):111-116 incorporated herein byreference. As an example of the invention, the spray drying processleads to co-precipitation of CaF₂ and NaCl in the form of a clusterconsisting of CaF₂ primary and discrete particles distributed in amatrix of NaCl. When exposed to an aqueous solution, the dissolution ofNaCl will lead to the dispersion of the solid primary CaF₂ particlesthat may be collected for appropriate therapeutic use. This method canproduce well dispersed, desirably sized nano CaF₂ primary particles,which can be used as a more effective anti-caries agent in rinses ordentifrices, for example.

The method also has application in the formation of other nanosizedparticulates of various compounds. Generally, the process involvessolubilizing appropriate precursor compounds in chosen solvents and thensimultaneously dry spraying the discrete solutions together to enablethe ionic components to interact or bond thereby forming compounds ofhighly different or distinct solubility. By spray drying the two andpossibly more solubilized compounds, agglomerated but discrete, solidnanoparticles are formed in a solid but soluble matrix. The matrix whichis formed has a solubility in a chosen solvent significantly greaterthan the particles, thus enabling collection of the discrete,agglomerated particles by dissolving the matrix and capturing theparticles.

Thus, it is an object of the invention to provide a method for theavoidance of agglomerated clusters of particles, such as CaF₂ particles,and thus provide particles generally of less than 50 nm in size (BETmeasurement) and 300 nm (dynamic light scattering (DLS) measurement).

It is a further object of the invention to provide a method forefficiently making calcium CaF₂ particles less than 300 nanometers (DLS)in size with greatly reduced agglomeration as a result of the processingsteps associated with the creation of such particles.

Yet another object of the invention is to provide techniques for thecreation of CaF₂ particles less than 300 nanometers (DLS) in size fortheir use to significantly increase remineralization effects of thefluoride treatment in effecting caries prevention.

Another object of the invention is to provide a method for makingdiscrete, solid particles of various compounds having a size ofnanometer dimension.

These and other objects, advantages and features of the invention willbe set forth in the detailed description which follows.

BRIEF DESCRIPTION OF THE DRAWING

In the detailed description which follows, reference will be made to thedrawing comprised of the following figures:

FIG. 1: X-ray diffraction (XRD) patterns of CaF2/NaCl composite nanoparticles prepared by spray drying techniques. 215×166 mm (600×600 DPI).

FIG. 2: Scanning electron microscope (SEM) morphology of nano CaF₂/NaClcomposite particles prepared by spray drying techniques wherein patternsa1, a2, a3 are respectively as-prepared CaF₂-1, CaF₂-2, CaF₂-3; andpatterns b1, b2, b3 are respectively CaF₂-1, CaF₂-2 and CaF₂-3redispersed in ethanol after washing with distilled water. 330×176 mm(72×72 DPI)>

FIG. 3: SEM and EDS of nano CaF₂/NaCl composite particles prepared byspray drying techniques: (a) as prepared sample (at ×5k), (b) washedsample (at ×5k), (c) SEM of a single nano cluster in as prepared sample(at ×70k), (d) EDS spectrum of the single nano cluster (area within therectangle shown in c). 294×128 mm (72×72 DPI).

FIG. 4: Particle size distribution graphs of a pure nano CaF₂ sample(CaF₂-0, (a) graph) and a distilled water-washed nano CaF₂₊NaClcomposite sample (CaF₂-3, (b) graph). 267×190 mm (600×600 DPI).

FIG. 5: Schematic drawings of (a) a composite cluster containing CaF₂nanoparticles in the matrix of NaCl, and (b) a cluster containing pureCaF₂ nanoparticles. 323×243 mm (600×600 DPI).

FIG. 6: Photograph of suspension of a blue dye—incorporated nanoamorphous HA (left); after centrifugation (right).

DESCRIPTION OF REPRESENTATIVE EMBODIMENTS OF THE INVENTION

The following examples of the process is directed to the manufacture ofdiscrete particles of CaF₂ having a size generally less than 300 nm andincludes the steps of (1) providing at least a first fluoride solutionand a discrete calcium solution, (2) simultaneously ejecting saidsolutions by means of a dual spray drying apparatus in a manner whereinthe spray is simultaneously ejected from the spray nozzle(s) in apattern that effectively co-mingles the sprayed solutions (3) collectingthe particulates resulting from the spray drying operation which are inview of the solutes chosen comprised of generally separate CaF₂particles in a soluble, biocompatible matrix, and (4) dissolving thematrix and collecting the CaF₂ particles. Enabling the process requiresappropriate choices of solvents and solutes based upon their ionicreactivity and compound solubility.

Example A Preparation of Nano CaF₂/NaCl Particles

The nano CaF₂/NaCl particles were prepared using the spray drying systemgenerally described in On the role of calcium fluoride in thecariostatic mechanism of fluoride. Acta Odontol Scan 1988; 46:341-345,incorporated herewith by reference In the preparation of pure nano CaF₂,a 4 mmol/L Ca(OH)₂ solution and an 8 mmol/L NH₄F solution were,following preparation, simultaneously fed to the 2-liquid nozzle of aspray drying apparatus. To incorporate NaCl, NaCl of concentrations of(1.4, and 16) mmol/L were added to both the NH₄F and Ca (OH₂) solutions,respectively. This led to the formation of (CaF₂+NaCl) composites withCaF₂/NaCl molar equivalent ratios of 4:1, 1:1, and 1:4, or mass ratios5.34, 1.31 and 0.33 (Table 1). Pure nano CaF₂ particles were alsoprepared as the control. All solutions were prepared using reagent gradechemicals and mole ratios of CaF₂/NaCl in the range of 10:1 to 1:10 areconsidered within the scope of the process.

The reaction of the solutions led to the formation of (CaF₂+NaCl)composite particles and NH₄F (Eqn. 1). The (CaF₂+NaCl) composite ofparticles and matrix was collected at the end of the process, while theNH₄OH was removed as NH₃ and H₂O vapors with the air flowCa(OH)₂+NH₄F+NaCl→CaF₂+NaCl+NH₃↑+H₂O↑  (Eqn. 1)

Microstructural Characterization of Nano CaF₂/NaCl Particles

The obtained nano powders were characterized by powder X-ray diffraction(XRD), DMAX 2200, Rigaku Denki, Woodlands, Tex.) for crystalline phaseidentification. Scans were performed between 10°<2θ<60°. The estimatedstandard uncertainty of the 2θ measurement is 0.01°. The morphology andcomposition of the initially collected particulate material (powder) wasexamined using scanning electron microscopy (SEM, JSM-5300, JEOL,Peabody, Mass.) and X-ray energy dispersive spectroscopy (XEDS, equippedin Hitachi S-4700 SEM, Pleasanton, Calif.). The SEM samples wereprepared by depositing the powder onto aluminum stubs or carbon tapes(to reduce the A1 interference in XEDS spectrum) from a well-sonicateddilute suspension in pure ethanol. The size distribution of the powderswas determined by dynamic light scattering (DLS, Zetaszier, MalvernInstrument, Westborough, Mass.) at a wavelength of 532 nm at 25° C.using a well-sonicated dilute suspension in distilled water (0.25 mg/mlCaF₂) as the only particulate matter in the suspension. In order to keepthe NaCl concentration constant for all suspensions, an appropriateamount of NaCl solid was added to each of the suspensions such that theNaCl concentration was the same as that in sample CaF₂-3 (12.8 mmol/L).

To investigate if the CaF₂ can be readily dispersed after the NaCl wasdissolved, samples of CaF₂/NaCl composite powders were washed withdistilled water first to dissolve the NaCl, and then centrifuged at(48,000 g) for 10 min (J2-21, Beckman, Brea, Calif.). The solidsediments which should consist of pure CaF₂ were then collected forpreparing well-sonicated dilute suspension in pure ethanol for SEMexamination and DLS measurement. The sediments were also dried in airfor BET and DLS characterization. Multipoint BET surface area analyseswere done with ultra high purity nitrogen as the adsorbate gas andliquid nitrogen as the cryogen (ASAP 2020 Surface Area & PorosityAnalyzer, Micromeritics, Norcross, Ga.). All samples were degassed at105° C. for 1 hour and then held at 105° C. for 2 hours with ultra highpurity nitrogen purge before the measurement. The estimated standarduncertainty of the BET measurement was 0.15% of the reading. Theparticle size of the primary crystals of CaF₂ was estimated from the BETsurface area by calculating equivalent spherical diameter, or BETparticle diameter (d_(BET)), from the fundamental equation: d_(BET)=6/(pS_(W)), where p is the theoretical density of the CaF₂ (3.14 g/cm³) andS_(W) is the specific surface area (see Ring, TA. Fundamentals ofCeramic Powder Processing and Synthesis. San Diego; Academic Press;1996).

XRD patterns of the obtained powders (FIG. 1) showed that the powdersinclude both CaF₂ and NaCl phases and their ratios corresponded to theones in the starting solution. No traces of other phases such asCa(OH)₂, NH₄F, CaCl₂ or NaF were detected. The peaks of the CaF₂ wererelatively broad compared to those of NaCl, suggesting a finer crystalsize or less perfect crystal structure for the CaF₂. The distilledwater-washed samples contained only CaF₂ as their XRD patterns (notshown) were similar to that of the CaF₂-0 sample, showing CaF₂ peaksthat are much broader when compared to those of the commercialmicro-sized CaF₂.

SEM examinations (FIG. 2) showed that the as-prepared powder ranged fromabout 50 nm to 800 nm in size. Also, these powders exhibited numerousspherical protuberances on the surfaces, suggesting that they wereformed during the spray drying process through aggregation of the muchsmaller primary particles. In strong contrast, after washing withdistilled water, the material dispersed into much small particles ofabout 100 nm or less (FIG. 2). The particles became better dispersedwith fewer and smaller agglomerates when a greater amount of NaCl wasincorporated in the composite clusters during the preparation, andsubsequently dissolved in the water. However, when the percentage ofNaCl incorporation was very high, such as in the case of sample CaF₂-3,some NaCl crystals could form separately, rather than as the part of thecomposite clusters (FIG. 2 (a3)). EDS indicated that the nano compositeclusters or powders in as-sprayed samples contained CA, F, Na, and Cl,confirming that the samples contained both CaF₂ and NaCl (FIG. 3).

In comparison, the washed samples contained essentially Ca and F only.However, the CaF₂/NaCl ratio in a single before-wash composite cluster(intensity of Ca/Na is≈2.7) appeared to be higher than the average ratio(intensity of Ca/Na is≈13) in the bulk sample, suggesting that theCaF₂/NaCl precipitation may not be homogeneous. This may also explainthe SEM observation that some NaCl precipitated as a separate phase asdescribed above.

The DLS measurement in 12.8 mmol/L NaCl solution (Table 2) showed thatthe mean particle size (z-average) of CaF₂ nanoparticles were greatlyreduced when the NaCl was co-precipitated during spray drying andsubsequently dissolved in water. The size reduction was greater whenmore NaCl was incorporated in the composite. The DLS measurement of thedistilled water-washed samples dispersed in ethanol (Table 2) showed asimilar trend, but the average sizes were smaller and closer to theparticle sized observed by SEM. FIG. 4 compares the representativeparticle size distribution of samples CaF₂-0 and CaF₂-3 (washed) inethanol. The pure CaF₂ sample exhibited a particle size distribution of(200 to 1000) nm with the median value at 425 nm, while the washedCaF₂-3 sample had a distribution of (45 to 200) nm with the median valueat 75 nm. These results, which were in good agreement with the SEMobservations, showed that the effective median particle size wasdecreased by nearly 6-fold. The BET specific surface areas of the washedCaF₂ powders ranged between (49 to 63) m²/g (Table 2) and the estimatedequivalent spherical particle sizes (d_(BET)) were (30 to 39) nm. Theselatter values were similar to the size of the primary particles observedin SEM (FIG. 3), suggesting that the BET particle size valuescorresponded to those of the primary particles, which were similar inall CaF₂ preparations with a mean value of (36±4) nm.

TABLE 1 Compositions of the starting solutions used for preparingnano-sized CaF₂/NaCl CaF₂/NaCl molar Ca(OH)₂ NH₄F NaCl equivalentCaF₂/NaCl Sample (mmol/L) (mmol/L) (mmol/L) ratio mass ratio CaF₂-0 2 40 CaF₂-1 2 4 1 4:1 5.34 CaF₂-2 2 4 4 1:1 1.33 CaF₂-3 2 16 1:4 0.33

TABLE 2 DLS particle size, BET specific surface area and degree ofagglomeration of nano CaF₂ Sample CaF₂-0 CaF₂-1 CaF₂-2 CaF₂-3 DLSZ-average particle size in 1015 ± 70 425 ± 6 367 ± 6 219 ± 4 12.8 mmol/Lwater solution, d_(DLS1) (nm) (n = 3) DLS Z-average particle size in 455± 6 246 ± 8 197 ± 5 158 ± 3 ethanol, d_(DLS2) (nm) (n = 3) BET specificsurface area, Sw 49 53 49 63 (m²/g) BET equivalent spherical 39 36 39 30particle size, d_(BET) (nm) Degree of Agglomeration 2020  319  164  85(DA)

Process Characterization

Due to the instantaneous atomization and drying process, the spraydrying technique makes it possible to co-precipitate two discrete phaseswith very different solubility into composite particles. To fullyunderstand the process, it is hypothesized that the following sequenceof events occurred within each droplet of atomized solution during thespray drying process when preparing pure CaF₂: (1) the mixed solution,i.e., Ca(OH)₂+NH₄F in Eqn.1, became progressively more supersaturatedwith respect to CaF₂ as water and NH₄OH were rapidly evaporated, (2)numerous CaF₂ nuclei were formed via homogenous nucleation, (3) thenuclei grew larger and closer to each other as the droplet dried out,and (4) formation of a cluster of tightly aggregated primary nanoparticles. It seems plausible that, as the droplet dries out, the verylast portion of the precipitated CaF₂ would form at the contact pointsof the primary particles, bridging them together to form a stable threedimensional network that would hinder ready dispersion of the clusterinto free primary particles. Therefore, if a highly soluble compound,such as NaCl, is co-precipitated with CaF₂ in the spray-drying process,NaCl precipitation will begin to occur only after formation of the CaF₂primary particles is nearly complete, i.e., after step (3) describedabove. In this case, NaCl instead of CaF₂ will be formed in the spacesbetween the CaF₂ primary particles, leading to formation of a clusterconsisting of CaF₂ primary particles distributed in a matrix of NaCl(FIG. 5 a) rather than a cluster of tightly interlocked CaF₂ particles(FIG. 5 b). When exposed to an aqueous solution, dissolution of NaClshould lead to dispersion of the CaF₂ particles.

The results (FIG. 1-3) show that CaF₂/NaCl composite particles aresuccessfully formed through the spray drying process, which has similarmorphology and particle size as the pure CaF₂ particles preparedpreviously, i.e., clusters of (50 to 800) nm, consisting of smallerprimary particles [11]. Once in the aqueous solution, the NaCldissolved, releasing the primary CaF₂ nanoparticles (FIG. 2). By thesemeans, better dispersed CaF₂ nanoparticles with a narrow sizedistribution (FIG. 2). By these means, better dispersed CaF₂nanoparticles with a narrow size distribution can be obtained (FIG. 2,4). A potential problem with this process is that multiple phases couldform due to the existence of several ions in the solution and the fastprecipitation in the spray drying process. XRD pattern of the obtainedpowders (FIG. 1), however, showed no traces of other phases such asCa(OH)₂, NH₄F, CaCl₂ or NaF This demonstrated that the least solublephase, i.e., CaF₂ will precipitate first, and the precipitation of thesoluble phases, i.e., NaCl, will begin to occur only after formation ofthe CaF₂ primary particles is nearly complete. These results supportedthe feasibility of the approach for preparing well-dispersed nanoparticles by incorporating a more soluble phase that can be dissolvedsubsequently.

Three characterization methods have been used in this study: SEMprovided a direct image of particle morphology, size, and degree ofparticle dispersion or agglomeration: DLS measured the particle sizedistribution in a liquid: BET determined the size of the primaryparticles. As the particle size measured by DLS is hydrodynamic diameterwithin a liquid, the results are very much affected by the liquid ormedium. Two media have been used in this study. The 12.8 mmol/L NaClsolution was used for all as-sprayed samples as sample CaF₂-3 containedthis amount of NaCl when dissolved in water. This medium is close to theone (1) mmol/L NaCl solution) recommended by the international standardfor DLS measurement. However, the particle sizes measured this way(Table 2) appeared to be larger when compared to the SEM observations. Aseparate DLS measurement of CaF₂-0 powders in distilled water only gavea value of (497±20) nm (n=3), suggesting that the concentration of thesalt in the medium played an important role in the measurement. Inaddition, to simulate the sample preparation for SEM, ethanol was alsoused as a medium for DLS measurement of all washed samples (no washingneeded for sample CaF₂-0). The particle sizes obtained by this methodwere much smaller compared to those measured in NaCl solution (Table 2).However, the results still seemed slightly larger than the SEMobservation, which may be due to both the nature of the technique andthe existence of negligible amounts of less dispersed particles thatcaused the small tail on the right side of the size distribution (FIG.4). In sum, the incorporation of NaCl during the preparation of CaF₂ ledto a well dispersed nano CaF₂ particles.

As shown in FIGS. 2 and 4 and Table 2, the degree of particle dispersionfor the washed samples increased with the percentage of NaClco-precipitated with CaF₂. This is reasonable as the primary CaF₂particles can be better distributed within a larger volume of the NaClmatrix. However, when the NaCl incorporation was too high, some NaClcrystals could precipitate early in the process, i.e., beforesignificant CaF₂ precipitation has occurred. Rapid growth of these NaClcrystals could occur simultaneously with the precipitation of CaF₂,forming a separate phase rather than as the matrix of the compositeclusters (FIG. 2 (a3)). This suggests that there is a limit for theincorporation of NaCl.

When there is particle agglomeration, the particle size estimated by theBET method is usually much smaller than by other methods, because BETmethods provide an approximate measure of the size of primary CaF₂particles rather than the true size of the agglomerated particles. Incontrast, particle size values obtained from the DLS measurements aremore closely related to the true physical size of the particles that mayhave various degrees of agglomeration. Thus, the degree of particledispersions/agglomeration can be assessed by comparing the valuesobtained by the BET and DLS methods. Assuming both the primary particlesand the agglomerated particles have spherical shapes and the primaryparticles and the agglomerated particles have spherical shapes and theprimary particles are closed packed in an agglomerated particle, we candefine the degree of agglomeration (DA) as the averaged number ofprimary particles contained in the agglomerated particles, which can beestimated by.DA=volume of composite cluster/volume of primary particle=(d _(DLs2)/d_(BET))³   (Eqn. 2)By using the mean primary particle size of 36 nm and the DLS Z-averageparticle size in ethanol, i.e., d_(DLs2) in Table 2, the DA valuesranged from 2020 for CaF₂-0 and 85 for CaF₂-3 Alternatively, if usingthe median particle size in FIG. 4, i.e., 425 nm for CaF₂-0 and 75 nmfor CaF₂-3, the DA values for CaF₂-0 and CaF₂-3 were respectively 1645and 9 These results suggest that our approach is very effective inobtaining better-dispersed nanoparticles. Nonetheless, there were stillnegligible amounts of less dispersed particles, as revealed by both DLSand SEM.

Example B Preparation of Nano Amorphous HA (Hydroxyapatite)

Nano particles of a composite consisting of HA, NaCl and Brilliant bluedye (CAS Registry Number: 3844-45-9) were synthesized by simultaneouslyfeeding to a two liquid nozzle (1) a solution containing 4 mM Ca(OH)₂and 3.44 mM NaCl, and (2) a solution containing 2.4 mM H₃PO₄ and 0.032g/L of blue dye and spray dried as previously described. The productwould have a HA:NaCl mass ratio of 2:1, and the blue dye content of 5mass %. The collected product was twice washed in distilled water (10mg/mL) to dissolve the NaCl followed by centrifugation. The supernatantwas essentially colorless (FIG. 6), indicating that little or no dye wasincorporated into the NaCl phase during the spray drying process. Thiswas expected because large dye molecule is likely to be excluded fromNaCl, which has a simple and tight crystal structure. In contrast, thenano amorphous HA particles showed a dark blue color indicating that thelarge dye molecules were trapped in the HA phase by co-precipitation.These results demonstrate using the technique to incorporate drugmolecules (analogous to the blue dye) in HA nano particles by the spraydrying method.

DLS measured particle size of the this HA was 228±8 nm (n=3), which issignificantly smaller than the size (380±49 nm) of a similarly preparedamorphous HA without the NaCl matrix reported by “Sun L M, Chow L C,Frukhtbeyn S A, Bonevich J E (2010): Preparation and Properties ofNanoparticles of Calcium Phosphates with Various Ca/P Ratios. J Res NatlInst Stand Technol 115: 243-255.”

It should be noted that, in addition to using NaCl as the matrix phase,other soluble compounds such as potassium nitrate, sodium fluoride,etc., can also be used to obtain similar results. In general, thistechnique can be used to produce better dispersed nanoparticles for anysystem as long a (1) the nanoparticles to be prepared are significantlyless soluble than the matrix material (on the order of at least 20 timesmore soluble), and (2) none of the constituents of the matrix materialwould produce undesired effects on the composition of the nanoparticlesbeing prepared.

This approach is, for example, applicable in preparing better-dispersedcalcium phosphate nanoparticles for drug delivery and gene therapy. Thatis, in the present invention, calcium fluoride, the nano particles to beprepared, has a solubility (in water) of about 0.018 g/L, whereas thatof the matrix, sodium chloride, is about 359 g/L. Similarly, solubilityof other calcium phosphates are approximately: DCPD (0.15 g/L), DCPA(0.074 g/L), ACP (0.021 g/L), and HA (0.00066 g/L). All of the abovehave solubility values over 1000 times smaller than that of sodiumchloride, therefore requirement (1) above is well satisfied. Sincesodium chloride would not significantly interact with calcium phosphateformation in the spray drying process, requirement (2) is also fullymet.

A large number of other compounds can also satisfy the two requirementsand are good candidates for use the matrix. Non-toxic and biocompatibleexamples may include mannitol, sucrose, when water is used as thesolvent in the spray drying process. If the nano particles to beprepared are not for biomedical uses, additional compounds can beinvolved.

While there has been set forth various embodiments of the invention andthe processes practiced, the invention is to be limited only by thefollowing claims and equivalents thereof.

What is claimed is:
 1. A method for preparation of discrete CaF₂nanoparticles comprising the steps of: a) providing a soluablebiocompatible salt and NH₄F first liquid solution; b) providing asoluble biocompatible salt and Ca(OH)₂ second liquid solution; c)simultaneously feeding the first and second solutions through a sprayvaporizing and drying apparatus to form a composite of CaF₂ particles ina salt matrix; and d) collecting the composite particles and matrix. 2.The method of claim 1 wherein the salt is NaCl.
 3. The method of claim 2wherein the molar ratios of CaF₂/NaCl are in the range of about 10:1 to1:10.
 4. The method of claim 3 wherein the molar ratios of CaF₂/NaCl arein the range of 4:1 to 1:4.
 5. The method of claim 1 wherein a solventof the first solution is selected from the group consisting of water,alcohols, acetone, alkylhalides, dimethylsulfoxide (DMSO) andcombinations thereof and a solvent of the second solution is selectedfrom the group consisting of water, alcohols, acetone, alkylhalides,dimethylsulfoxide (DMSO) and combinations thereof.
 6. The method ofclaim 1 including the step of separating the particles and matrix bydissolution of the matrix and collecting the particles.
 7. A method forpreparation of discrete, generally unagglomerated nanoparticles of CaF₂comprising the steps of: (a) simultaneously spraying a first liquidsolution and a second liquid solution into the same region having adrying gas atmosphere maintained at an ambient pressure and temperature,said first solution comprising NH₄F, a biocompatible solvent and asolubilized salt selected from the group consisting of a biocompatibleanionic salt and combinations of anionic biocompatible salts that aremore soluble than CaF₂ in the same solvent, and said second solutioncomprising a solubilized biocompatible calcium compound essentially freeof F; (b) deliquifying the resultant combined spray to form CaF₂particles in a matrix of said soluble salt, the solubility of said saltgreater than the solubility of said CaF₂ in a solvent of said salt; (c)liquefying the matrix with said solvent; and (d) separating the CaF₂particles from the liquefied matrix solution.
 8. A method forpreparation of discrete nanosized particles of a soluble ionic compoundcomprising the steps of: (a) forming a first solution of an anion sourceof said compound and a first salt; (b) forming a second solution of acation source of said compound and a second salt, said salts being moresoluble than said compound in the same solvent; (c) simultaneously spraydrying said solutions together to form said compound in the form ofnanosized particles in a matrix of said salt; and (d) dissolving thematrix.
 9. The method of claim 8 wherein the first and second salts areidentical.
 10. The method of claim 8 wherein the anion source is NH₄F,the cation source is Ca(OH)₂, the salt is NaCl and the solvent is water.11. The method of claim 8 wherein the solubility of the salt is at leastabout 20 times the solubility of the compound.